RESUMEN
Following the cloning and characterization of the transient receptor potential vanilloid 1 (TRPV1), a growing body of research has identified the important role of TRPV1 and related channels in diverse physiological functions including temperature transduction and pain signalling. As a result, there has been a great deal of interest by the pharmaceutical industry to develop small molecule modulators of the activity of these channels for potential therapeutic use. While most of the efforts have focused on examining the role of TRPV1 in nociception, more recent work has begun to assess the therapeutic utility of targeting other TRP channels. This manuscript is aimed at introducing the reader of this special issue to the promising new developments and findings as well as emerging challenges in the targeting of the thermoTRP family of receptors for clinical therapeutic use. This chapter will focus on current efforts from the pharmaceutical industry to develop highly potent and efficacious compounds that modulate TRP channel function. In particular, this chapter will highlight recent drug discovery activities around the transient receptor potential vanilloid family members TRPV1, TRPV3, and TRPV4, the transient receptor potential ankyrin family member TRPA1, and the transient receptor potential melastatin family member TRPM8. The majority of the work included in this chapter will focus on recent findings in the development of TRP modulators for pain indications; however, for certain targets where data exist, other indications will be discussed. The increasing number of small biotech and pharmaceutical companies pursuing targets in these families of ion channels highlights the perceived importance of these targets in the treatment of a variety of disease states including inflammatory and neuropathic pain, urinary incontinence, painful bladder syndrome, and even types of prostate cancer.
Asunto(s)
Dolor/tratamiento farmacológico , Canales de Potencial de Receptor Transitorio/antagonistas & inhibidores , Animales , Descubrimiento de Drogas , Humanos , Dolor/complicaciones , Dolor/metabolismoRESUMEN
BACKGROUND: Safe and effective treatment for chronic inflammatory and neuropathic pain remains a key unmet medical need for many patients. The recent discovery and description of the transient receptor potential family of receptors including TRPV1 and TRPA1 has provided a number of potential new therapeutic targets for treating chronic pain. Recent reports have suggested that TRPA1 may play an important role in acute formalin and CFA induced pain. The current study was designed to further explore the therapeutic potential of pharmacological TRPA1 antagonism to treat inflammatory and neuropathic pain. RESULTS: The in vitro potencies of HC-030031 versus cinnamaldehyde or allyl isothiocyanate (AITC or Mustard oil)-induced TRPA1 activation were 4.9 +/- 0.1 and 7.5 +/- 0.2 microM respectively (IC50). These findings were similar to the previously reported IC50 of 6.2 microM against AITC activation of TRPA1 1. In the rat, oral administration of HC-030031 reduced AITC-induced nocifensive behaviors at a dose of 100 mg/kg. Moreover, oral HC-030031 (100 mg/kg) significantly reversed mechanical hypersensitivity in the more chronic models of Complete Freunds Adjuvant (CFA)-induced inflammatory pain and the spinal nerve ligation model of neuropathic pain. CONCLUSION: Using oral administration of the selective TRPA1 antagonist HC-030031, our results demonstrated that TRPA1 plays an important role in the mechanisms responsible for mechanical hypersensitivity observed in inflammatory and neuropathic pain models. These findings suggested that TRPA1 antagonism may be a suitable new approach for the development of a potent and selective therapeutic agent to treat both inflammatory and neuropathic pain.
Asunto(s)
Acetanilidas/farmacología , Analgésicos/farmacología , Canales de Calcio/fisiología , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/fisiología , Neuralgia/tratamiento farmacológico , Dolor/tratamiento farmacológico , Purinas/farmacología , Canales de Potencial de Receptor Transitorio/antagonistas & inhibidores , Canales de Potencial de Receptor Transitorio/fisiología , Animales , Ancirinas , Línea Celular , Modelos Animales de Enfermedad , Humanos , Inflamación , Masculino , Neuralgia/etiología , Neuralgia/patología , Dolor/etiología , Dolor/patología , Ratas , Ratas Sprague-Dawley , Canal Catiónico TRPA1 , Canales Catiónicos TRPCRESUMEN
The clinical use of TRPV1 (transient receptor potential vanilloid subfamily, member 1; also known as VR1) antagonists is based on the concept that endogenous agonists acting on TRPV1 might provide a major contribution to certain pain conditions. Indeed, a number of small-molecule TRPV1 antagonists are already undergoing Phase I/II clinical trials for the indications of chronic inflammatory pain and migraine. Moreover, animal models suggest a therapeutic value for TRPV1 antagonists in the treatment of other types of pain, including pain from cancer. We argue that TRPV1 antagonists alone or in conjunction with other analgesics will improve the quality of life of people with migraine, chronic intractable pain secondary to cancer, AIDS or diabetes. Moreover, emerging data indicate that TRPV1 antagonists could also be useful in treating disorders other than pain, such as urinary urge incontinence, chronic cough and irritable bowel syndrome. The lack of effective drugs for treating many of these conditions highlights the need for further investigation into the therapeutic potential of TRPV1 antagonists.
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Trastornos Migrañosos/tratamiento farmacológico , Dolor/tratamiento farmacológico , Canales Catiónicos TRPV/antagonistas & inhibidores , Canales Catiónicos TRPV/genética , Analgésicos/uso terapéutico , Animales , Clonación Molecular , Glucosa/metabolismo , Humanos , Enfermedades Musculares/tratamiento farmacológico , Enfermedades de la Piel/tratamiento farmacológico , Canales Catiónicos TRPV/agonistas , Canales Catiónicos TRPV/fisiología , Enfermedades Urológicas/tratamiento farmacológicoRESUMEN
Garlic's pungent flavor has made it a popular ingredient in cuisines around the world and throughout history. Garlic's health benefits have been elevated from folklore to clinical study. Although there is some controversy as to the efficacy of garlic, garlic products are one of the most popular herbal supplements in the U.S. Chemically complex, garlic contains different assortments of sulfur compounds depending on whether the cloves are intact, crushed, cooked, or raw. Raw garlic, when cut and placed on the tongue or lips, elicits painful burning and prickling sensations through unknown mechanisms. Here, we show that raw but not baked garlic activates TRPA1 and TRPV1, two temperature-activated ion channels that belong to the transient receptor potential (TRP) family. These thermoTRPs are present in the pain-sensing neurons that innervate the mouth. We further show that allicin, an unstable component of fresh garlic, is the chemical responsible for TRPA1 and TRPV1 activation and is therefore likely to cause garlic's pungency.
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Canales de Calcio/efectos de los fármacos , Ajo/química , Canales Iónicos/metabolismo , Neuronas/efectos de los fármacos , Ácidos Sulfínicos/farmacología , Animales , Ancirinas , Células CHO , Canales de Calcio/metabolismo , Células Cultivadas , Cricetinae , Cricetulus , Disulfuros , Relación Dosis-Respuesta a Droga , Electrofisiología , Fluorometría , Espectroscopía de Resonancia Magnética , Neuronas/metabolismo , Extractos Vegetales , Ratas , Ácidos Sulfínicos/metabolismo , Canal Catiónico TRPA1 , Canales Catiónicos TRPC , Canales Catiónicos TRPVRESUMEN
Six members of the mammalian transient receptor potential (TRP) ion channels respond to varied temperature thresholds. The natural compounds capsaicin and menthol activate noxious heat-sensitive TRPV1 and cold-sensitive TRPM8, respectively. The burning and cooling perception of capsaicin and menthol demonstrate that these ion channels mediate thermosensation. We show that, in addition to noxious cold, pungent natural compounds present in cinnamon oil, wintergreen oil, clove oil, mustard oil, and ginger all activate TRPA1 (ANKTM1). Bradykinin, an inflammatory peptide acting through its G protein-coupled receptor, also activates TRPA1. We further show that phospholipase C is an important signaling component for TRPA1 activation. Cinnamaldehyde, the most specific TRPA1 activator, excites a subset of sensory neurons highly enriched in cold-sensitive neurons and elicits nociceptive behavior in mice. Collectively, these data demonstrate that TRPA1 activation elicits a painful sensation and provide a potential molecular model for why noxious cold can paradoxically be perceived as burning pain.
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Acroleína/análogos & derivados , Acroleína/farmacología , Bradiquinina/farmacología , Frío/efectos adversos , Canales Iónicos/efectos de los fármacos , Canales Iónicos/metabolismo , Neuronas Aferentes/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Células CHO , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Cricetinae , Relación Dosis-Respuesta a Droga , Humanos , Mediadores de Inflamación/farmacología , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Ratones , Neuronas Aferentes/metabolismo , Nociceptores/efectos de los fármacos , Nociceptores/metabolismo , Dolor/inducido químicamente , Dolor/metabolismo , Dolor/fisiopatología , Dimensión del Dolor/efectos de los fármacos , Ratas , Canal Catiónico TRPA1 , Canales de Potencial de Receptor Transitorio , Fosfolipasas de Tipo C/metabolismoRESUMEN
Mammals detect temperature with specialized neurons in the peripheral nervous system. Four TRPV-class channels have been implicated in sensing heat, and one TRPM-class channel in sensing cold. The combined range of temperatures that activate these channels covers a majority of the relevant physiological spectrum sensed by most mammals, with a significant gap in the noxious cold range. Here, we describe the characterization of ANKTM1, a cold-activated channel with a lower activation temperature compared to the cold and menthol receptor, TRPM8. ANKTM1 is a distant family member of TRP channels with very little amino acid similarity to TRPM8. It is found in a subset of nociceptive sensory neurons where it is coexpressed with TRPV1/VR1 (the capsaicin/heat receptor) but not TRPM8. Consistent with the expression of ANKTM1, we identify noxious cold-sensitive sensory neurons that also respond to capsaicin but not to menthol.
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Canales de Calcio/metabolismo , Frío , Neuronas Aferentes/metabolismo , Nociceptores/metabolismo , Termorreceptores/metabolismo , Canales de Potencial de Receptor Transitorio/metabolismo , Secuencia de Aminoácidos , Animales , Ancirinas/química , Células CHO , Capsaicina/farmacología , Células Cultivadas , Cricetinae , Femenino , Proteínas de la Membrana/química , Ratones , Datos de Secuencia Molecular , Proteínas del Tejido Nervioso/metabolismo , Estructura Terciaria de Proteína , Ratas , Ratas Sprague-Dawley , Canal Catiónico TRPA1 , Canales Catiónicos TRPC , Termorreceptores/químicaRESUMEN
Plasma membrane proteins of the solute carrier family 5 (SLC5) are responsible for sodium-coupled uptake of ions, sugars and nutrients in the vertebrate body. Mutations in SLC5 genes are the cause of several inherited human disorders. We have recently reported the cloning and transport properties of SGLT-1L, a Xenopus homologue of the sodium-dependent glucose cotransporter 1 (SGLT-1) [Nagata et al. (1999) Am. J. Physiol. 276: G1251 -G 1259]. Here, we describe the phylogenetic relationship of SGLT-1L with other members of the SLC5 family and characterize its expression during Xenopus embryogenesis and in organ cultures. Sequence comparisons and phylogenetic analyses of all known vertebrate SLC5 sequences indicated that Xenopus SGLT-1L encodes a novel SLC5 member, which shares highest amino acid identity with mammalian ST-1 proteins. Temporal and spatial expression of SGLT-1L during Xenopus embryogenesis was examined by whole mount in situ hybridization. Initiation of SGLT-1L expression occurred in the late tailbud embryo. Remarkably, expression was restricted to the developing pronephric kidney. SGLT-1L was highly expressed in tubular epithelia, but completely absent from the epithelia of the duct. Analysis of growth factor-treated animal caps indicated that expression of SGLT-1L could also be induced in organ cultures. Taken together, our findings indicate that the expression of sodium-dependent solute cotransporter genes in early segments of the excretory system appears to be conserved between pronephric and metanephric kidneys. Furthermore, we establish SGLT-1L as a novel, highly specific molecular marker for pronephric tubule epithelia undergoing maturation and terminal differentiation in Xenopus.